Connective tissue growth factor antagonizes transforming growth factor-β1/Smad signalling in renal mesangial cells

Abstract

The critical involvement of TGF-β1 (transforming growth factor-β1) in DN (diabetic nephropathy) is well established. However, the role of CTGF (connective tissue growth factor) in regulating the complex interplay of TGF-β1 signalling networks is poorly understood. The purpose of the present study was to investigate co-operative signalling between CTGF and TGF-β1 and its physiological significance. CTGF was determined to bind directly to the TβRIII (TGF-β type III receptor) and antagonize TGF-β1-induced Smad phosphorylation and transcriptional responses via its N-terminal half. Furthermore, TGF-β1 binding to its receptor was inhibited by CTGF. A consequent shift towards non-canonical TGF-β1 signalling and expression of a unique profile of differentially regulated genes was observed in CTGF/TGF-β1-treated mesangial cells. Decreased levels of Smad2/3 phosphorylation were evident in STZ (streptozotocin)-induced diabetic mice, concomitant with increased levels of CTGF. Knockdown of TβRIII restored TGF-β1-mediated Smad signalling and cell contractility, suggesting that TβRIII is key for CTGF-mediated regulation of TGF-β1. Comparison of gene expression profiles from CTGF/TGF-β1-treated mesangial cells and human renal biopsy material with histological diagnosis of DN revealed significant correlation among gene clusters. In summary, mesangial cell responses to TGF-β1 are regulated by cross-talk with CTGF, emphasizing the potential utility of targeting CTGF in DN.

Anti-Connective Tissue Growth Factor Antibody Treatment Reduces Extracellular Matrix Production in Trabecular Meshwork and Lamina Cribrosa Cells

“…In summary, recent studies have described the complex relationship between increased CTGF expression, TGFb activity, and fibrotic pathogenesis, 45,69,70 highlighting the complex signaling interplay between CTGF and TGFb that results in increased production of ECM components. It is now clear that the fibrotic/permissive microenvironment in the glaucoma AqH contains sizable quantities of both factors.…”

Renal Vascular Structure and Rarefaction

“…The mechanisms behind MV dysfunction, damage, and loss in the diabetic kidney are likely the result of concurrent insults such as hyperglycemia-induced renal vascular endothelial dysfunction (66), MV insulin resistance (94), augmented advanced-glycation end products (which reduce NO bioavailability leading to sustained vasoconstriction), increased secretion of cytokines and growth factors (120,132), and diminished ECM turnover (108). In the kidney, diabetes induces significant and progressive changes in the glomerular and tubulointerstitial capillary network.…”

TGFβ and CCN2/CTGF mediate actin related gene expression by differential E2F1/CREB activation

“…CCN2 has been reported to regulate TGFβ superfamily signalling in various contexts including renal mesangial/epithelial cell dysfunction [12,13] and DN [14]; coordinate expression of TGFβ and CCN2 has been demonstrated in glomerulonephritis and DN [15] and the cooperative nature of TGFβ and CCN2 in the promotion of fibrosis in animal models has been established [16]. …”